TGx-DDI, a Transcriptomic Biomarker for Genotoxicity Hazard Assessment of Pharmaceuticals and Environmental Chemicals
Heng-Hong Li1, Carole L Yauk2, Renxiang Chen1,3
1Department of Oncology, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, United States.
Abstract:
Genotoxicity testing is an essential component of the safety assessment paradigm required by regulatory agencies world-wide for analysis of drug candidates, and environmental and industrial chemicals. Current genotoxicity testing batteries feature a high incidence of irrelevant positive findings-particularly for in vitro chromosomal damage (CD) assays. The risk management of compounds with positive in vitro findings is a major challenge and requires complex, time consuming, and costly follow-up strategies including animal testing. Thus, regulators are urgently in need of new testing approaches to meet legislated mandates. Using machine learning, we identified a set of transcripts that responds predictably to DNA-damage in human cells that we refer to as the TGx-DDI biomarker, which was originally referred to as TGx-28.65. We proposed to use this biomarker in conjunction with current genotoxicity testing batteries to differentiate compounds with irrelevant "false" positive findings in the in vitro CD assays from true DNA damaging agents (i.e., for de-risking agents that are clastogenic in vitro but not in vivo). We validated the performance of the TGx-DDI biomarker to identify true DNA damaging agents, assessed intra- and inter- laboratory reproducibility, and cross-platform performance. Recently, to augment the application of this biomarker, we developed a high-throughput cell-based genotoxicity testing system using the NanoString nCounter® technology. Here, we review the status of TGx-DDI development, its integration in the genotoxicity testing paradigm, and progress to date in its qualification at the US Food and Drug Administration (FDA) as a drug development tool. If successfully validated and implemented, the TGx-DDI biomarker assay is expected to significantly augment the current strategy for the assessment of genotoxic hazards for drugs and chemicals.
Insights
A new biomarker, TGx-DDI, uses machine learning to identify true DNA-damaging agents, reducing false positives in genotoxicity testing. This approach aims to improve chemical and drug safety assessments, potentially decreasing the need for animal testing.
Area of Science:
- Toxicology
- Biomarker Discovery
- Computational Biology
Background:
- Genotoxicity testing is crucial for regulatory safety assessments of drugs and chemicals.
- Current *in vitro* chromosomal damage (CD) assays often yield irrelevant positive findings, necessitating complex and costly follow-up studies.
- There is an urgent need for improved genotoxicity testing strategies to meet regulatory requirements and reduce animal testing.
Purpose of the Study:
- To introduce and validate the TGx-DDI biomarker for differentiating true DNA-damaging agents from compounds with irrelevant *in vitro* findings.
- To assess the performance, reproducibility, and cross-platform capabilities of the TGx-DDI biomarker.
- To review the development status and regulatory progress of the TGx-DDI assay as a drug development tool.
Main Methods:
- Machine learning was employed to identify a set of transcripts (TGx-DDI biomarker) responsive to DNA damage in human cells.
- The TGx-DDI biomarker was validated for its ability to identify true DNA-damaging agents.
- Intra- and inter-laboratory reproducibility and cross-platform performance were assessed.
- A high-throughput cell-based genotoxicity testing system using NanoString nCounter® technology was developed.
Main Results:
- The TGx-DDI biomarker was identified and validated to accurately detect DNA-damaging agents.
- The assay demonstrated good reproducibility across different laboratories and platforms.
- The TGx-DDI assay, integrated with current testing batteries, can help de-risk compounds with false positive *in vitro* results.
- Progress has been made in qualifying the TGx-DDI assay at the US Food and Drug Administration (FDA).
Conclusions:
- The TGx-DDI biomarker offers a promising approach to improve the accuracy and efficiency of genotoxicity testing.
- Implementation of the TGx-DDI assay is expected to significantly enhance the assessment of genotoxic hazards for drugs and chemicals.
- This biomarker has the potential to reduce reliance on animal testing and streamline the drug development process.
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